Project Summary: RDC-0313-buprenorphine for Cocaine Abuse Cocaine abuse represents a major public health problem and a clear unmet medical need. In 2008, it was estimated that over 663,000 persons were treated for cocaine abuse. Presently there are no FDA approved medications to treat cocaine addiction. Recent clinical studies have demonstrated a significant reduction in cocaine-positive urine samples in patients receiving buprenorphine in combination with naltrexone compared to controls. These results suggest that a functional ORL1/nociceptin partial agonist with ?-opioid antagonism (i.e., buprenorphine), in the absence of -opioid receptor activation (i.e., naltrexone), may be a desired pharmacologic profile for the treatment of cocaine dependence. However, co-formulation of buprenorphine and naltrexone is impractical due to pharmacokinetic, pharmacodynamic and physiochemical limitations. RDC-0313 is a new chemical entity that acts primarily as an antagonist at opioid receptors, with mixed agonist/antagonist activity at ? and d receptors. RDC-0313 exhibits novel in vitro pharmacology and in vivo pharmacodynamics in nonclinical behavioral models. Importantly, RDC-0313 has demonstrated high oral and sublingual bioavailability and potent and sustained blockade of opioid agonism in man. These observations, along with favorable formulation characteristics, make RDC-0313 ideal for co-formulation with buprenorphine as a single sublingual tablet. A drug-drug interaction study of buprenorphine co-administered with and without sublingual administration of RDC-0313 is underway in collaboration with NIDA to determine the safety and tolerability of the co-administration and to demonstrate the blockade of buprenorphine agonism by RDC-0313. The goal of this work is to further advance the clinical development of a potential combination medication for cocaine dependence composed of RDC-0313 and buprenorphine. The four specific aims for this research program are completion of 1) Formulation development work to support Phase 1 and Phase 2 clinical investigation including development and production of a sublingual placebo tablet and development of a sublingual tablet of the RDC-0313-buprenorphine co-formulation, 2) a repeat-dose clinical trial to evaluate the safety and tolerability of co-administered RDC-0313-buprenorphine in the presence of cocaine, and to examine pharmacodynamic end-points associated with both buprenorphine and cocaine, 3) a nonclinical safety study of the proposed sublinqual co-formulation and 4) preparation of an IND for RDC-0313-buprenorphine for the treatment of cocaine dependence. Upon completion of this work, the safety, tolerability and mechanisms of a novel pharmacologic treatment for cocaine abuse will be better understood. Further a combination sublingual tablet will be available for Phase 2 clinical investigation under an IND for the treatment of cocaine dependence. PUBLIC HEALTH RELEVANCE: Cocaine abuse represents a major public health problem and a clear unmet medical need. Presently there are no FDA approved medications to treat cocaine addiction. The goal of this work is to further advance the clinical development of a potential combination medication for cocaine abuse composed of RDC-0313, a novel opioid modulator, and buprenorphine.